Defective DNA mismatch repair and XRCC2 mutation in uterine carcinosarcomas

A frameshift mutation in the double-strand breakage repair gene XRCC2 was identified in a mismatch repair (MMR) deficient cell line derived from a uterine carcinosarcoma. The frameshift mutation occurred in a mononucleotide run (poly-T tract), a target for strand-slippage mutation in MMR deficient tumors. We sought to determine if XRCC2 mutation is important to uterine carcinosarcoma tumorigenesis and whether the XRCC2 poly-T tract is a target for mutation in cells lacking MMR.

MSI-typing was used to assess the MMR status of 30 primary carcinosarcomas. The entire XRCC2 coding region was sequenced in all tumors. Single strand conformational variant (SSCV) analysis was used to screen for poly-T tract mutation in 50 endometrioid adenocarcinomas with defective MMR.

Seven of 30 (23.3%) primary carcinosarcomas had an MSI-H phenotype. No XRCC2 coding mutations were identified in the 30 carcinosarcomas, and only one of the fifty MSI-H endometrioid adenocarcinomas had an XRCC2 poly-T tract mutation.

Despite the high frequency of mismatch repair deficiency in carcinosarcomas, no XRCC2 poly-T tract frameshift mutations were identified in these tumors. The fact that only one of 50 additional MSI-H tumors had a frameshift mutation suggests that the XRCC2 poly-T tract is not a frequent target for defective MMR. The absence of coding sequence mutations in primary carcinosarcomas suggests that XRCC2 defects are unlikely to play a significant role in carcinosarcoma tumorigenesis.